PROJECT SUMMARY Alterations in protein quality control (also known as proteostasis) are a key feature of Alzheimer?s disease brains, and autophagy, a lysosomal-mediated degradation pathway, is significantly impacted in AD. Importantly, while the importance of autophagy to health and disease is well documented, how this process is regulated in a whole organism context remains poorly understood. Individual organs in the body, particularly skeletal muscle, seem to play a pivotal role in regulating proteostasis and autophagy in other tissues; including the CNS. This project investigates the role of skeletal muscle Transcription factor E-B (TFEB), a master regulator of autophagy and cellular clearance, in regulating CNS proteostasis during Alzheimer's disease. We will perform cutting-edge parabiosis paradigms and transcriptome analyses to dissect this muscle-to-brain axis in mouse models of enhanced skeletal muscle proteostasis, Alzheimer's disease and tau proteotoxicity. In collaboration with the University of Kansas Alzheimer's Disease Center, we will also examine proteostasis function in skeletal muscle samples from AD patients, with the goal of identifying novel peripheral biomarkers for AD. These studies will address muscle-to-brain cell-nonautonomous proteostasis signaling and uncover novel pathways promoting neuroprotection in the context of Alzheimer's disease, which will be crucial for therapy development for neurodegenerative disorders associated with dysfunctional proteostasis.